A person's immune system makes antibodies to attack germs such as bacteria or viruses, but it will not attack neuroblastoma because the tumor is part of our own bodies. An antibody that attaches to neuroblastoma can be made in a laboratory and then given intravenously to a patient. This antibody will circulate in the bloodstream until it finds and attaches to a neuroblastoma cell. And then the patient's own immune system will attack and kill that neuroblastoma cell.
3F8 is the name of a substance called a monoclonal antibody. It attaches to GD2, which is a marker on the surface of neuroblastoma cells. 3F8 was produced by white blood cells of mice, and it must be carefully prepared for human use. 3F8 is part of our standard treatment for high-risk neuroblastoma.
When 3F8 is injected into the bloodstream, it travels through the body until it attaches to the marker GD2 that is present on all neuroblastoma cells. The attachment of 3F8 to a neuroblastoma cell signals the patient's own immune system (e.g. the white blood cells) to treat neuroblastoma cells as foreign. In other words, the 3F8 directs the patient's immune system, which ordinarily acts only to control infections, to attack neuroblastoma cells and kill them. The treatment is effective even when a patient's immune system has been weakened by chemotherapy treatments because chemotherapy does not affect the part of the immune system that responds to 3F8 antibodies. Over time, as the body's immune system becomes stronger, 3F8 treatments may help the body learn to fight tumors on its own.
When 3F8 is injected into the body, we attach a radioactive isotope called 131-iodine (131I) or 124-iodine (124I). A gamma camera or a PET scanner is then used to scan the patient's body, allowing us to see radioactivity (from the radioactive iodine) in areas with neuroblastoma, but not in parts of the body in which neuroblastoma cells are not present.
Since 1987, over 30,000 infusions of 3F8 have been safely used in more than 500 patients. During this time, we have continued to make improvements to the effectiveness of 3F8 in killing neuroblastoma.
We have a number of different 3F8 protocols available at any given time, each of which is the subject of a clinical trial. Patients are recruited for clinical trials every one to three months. Availability of particular protocols will depend in part on when the patient is ready to begin treatment.
As of early 2008, we are offering three primary protocols:
For patients who are in near-complete or complete remission after induction therapy, 3F8 treatment is combined with GM-CSF (a protein that enhances the functioning of 3F8). This is a phase II trial that builds on previous trials that have shown promise. See Protocol 03-077 for more details.
For patients who have disease present after induction therapy but no progression, protocol 03-077 and other protocols described below may be appropriate, depending on the particular circumstances of the patient.
For patients who do not show sufficient improvement after induction therapy or whose neuroblastoma has recurred or progressed, there are phase I trials that may be appropriate.
The first protocol, sometimes referred to as “dose escalated” 3F8, combines 3F8 with GM-CSF. This trial seeks to maximize the efficacy of 3F8 by determining the highest dose of 3F8 that can be given safely to patients.
The second protocol, often referred to as hot antibodies, couples 3F8 and radioactive iodine. This treatment uses 3F8 to seek out and attach to tumor cells and then to deliver radiation directly to kill the cells without damaging normal tissues.
We have a number of 3F8 protocols for patients with high-risk neuroblastoma, including patients with bone marrow disease, bone disease, bulky disease (i.e., solid tumors), and relapsed and refractory disease. See the previous Q&A for an overview of the protocols and eligibility. Our clinical trial database also has information about specific protocols, including eligibility. The brief descriptions provided in the Q&A above and in the online clinical trial database are very general. Each patient must be evaluated to determine which protocol would likely be most effective for him or her. When necessary, we can customize a treatment regimen for individual patients, calling on many modalities, including chemotherapy, surgery, and radiation, to optimize the 3F8 treatment.
3F8 is given intravenously through a Broviac, Hickman, MediPort, or peripheral line (all means of injecting substances into the bloodstream) on an outpatient basis. When being treated with 3F8, patients usually need to be in the clinic for about three hours. This includes time for giving medicines to prevent possible side effects, the 30-minute 3F8 treatment, and one to two hours to monitor the patient for side effects. 3F8 treatment is provided in one- or two-week cycles.
3F8 treatment is provided in what are referred to as rounds or cycles of one- or two-week periods of daily infusions (except weekends), approximately three weeks off in between rounds. The number of rounds of 3F8 treatment will vary depending upon the protocol, but typically patients will receive at least two to four rounds. The primary consideration in determining the length of 3F8 treatment is that we want patients to receive at least 400 mg/m2 of 3F8 before developing human anti-mouse antibodies (HAMA) to the 3F8. See below for more information about HAMA.
Pain is the main side effect. All patients have pain. The second most common side effect is rash (hives with itching), which is an allergic reaction. Pain can lead to a fast pulse (rapid heart rate) and sometimes causes high blood pressure for a short period. Less-common side effects include fever, vomiting, and diarrhea. These problems can usually be taken care of in the outpatient clinic, but sometimes a patient needs to be admitted to the hospital for an overnight stay. In the neuroblastoma outpatient clinic at Memorial Sloan Kettering, we routinely treat 10 to 12 patients a day with 3F8, and manage side effects of the treatment without much difficulty.
3F8 attaches to GD2, which is present on some nerve cells as well as on neuroblastoma cells. When 3F8 attaches to a nerve cell, a message is sent to the brain, and the patient feels pain. The pain usually starts toward the middle or end of the daily 3F8 treatment and lasts a short time (usually from a few minutes up to an hour). Sometimes discomfort or minimal pain continues during the hours after the treatment. Medicines are used to prevent or control the pain (usually morphine or Dilaudid) and the allergic reactions (usually Benadryl or Vistaril). Ativan and Zofran are other medicines that can help. Patients who were treated with 3F8 beginning in 1986 have been followed, and to date, no permanent side effects on their nerves have appeared.
HAMA stands for “human anti-mouse antibodies.” HAMA measures how strongly the body's immune system is reacting to 3F8. 3F8, like most monoclonal antibodies, comes from the white blood cells of a mouse. This means that 3F8 looks different from a human antibody, and thus patients will eventually form antibodies (HAMA) against 3F8. Once a patient has developed HAMA, 3F8 treatments no longer effective because the HAMA blocks the 3F8 from getting to neuroblastoma cells. If the patient has received the desired amount of 3F8 (see next question for further information) by the time HAMA has developed, then treatment with 3F8 will be discontinued. However, if the patient has not yet received the desired amount, it is possible that HAMA may recede, and in that case we can resume 3F8 treatments. We conduct a blood test for HAMA usually one to two weeks after each round of 3F8 infusions. Patients with HAMA usually do not have pain or other side effects from 3F8 treatment.
HAMA is a positive sign in that it may mean the patient is developing an immune response against the neuroblastoma. However, when HAMA develops before the patient has received the usual 400 mg/m2 of 3F8 (two to four cycles), it may interrupt treatment. (As noted above, once HAMA is present, the 3F8 treatment is no longer effective.) Once HAMA has receded, treatment can resume. Most patients who have received chemotherapy only a short time before 3F8 treatment do not produce HAMA because part of their immune system is too suppressed. In these cases, 3F8 treatment will usually continue for up to two years. The aim of our protocols is to give repeated treatments with 3F8 until HAMA is made, because we believe that approach yields the best chances for cure. We continue to study HAMA to get a better understanding of how it may hurt or benefit patients in the long term.
No. An outside company produces it for us under GMP (good manufacturing practice) conditions. Private funding from foundations and philanthropic benefactors has been critical in paying for the production of 3F8 and for carrying out tests to meet the many governmental safety requirements. We do not charge our patients for 3F8. While we have been successful in getting government funding for much of our laboratory science, the government does not support the manufacturing process for 3F8. It is our hope that 3F8 will soon become a licensed drug.
Yes, as long as they meet the eligibility requirements of the individual treatment protocols.
There are a number of phase I and phase II studies, as well as state-of-the-art chemotherapy currently being offered at Memorial Sloan Kettering. Several promising approaches are in the pipeline waiting to be introduced into the clinic. See our clinical trial database for current information.